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Imidazo [4,5-c]quinoline derivatives and their use in the treatment of tumors and/or inflammation

Inactive Publication Date: 2012-05-03
PIRAMAL ENTERPRISES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025]According to another aspect of the present invention there is provided a method for treatment of cancer comprising administering to a mammal in need thereof a therapeutically effective amount of compounds of formula (I).
[00

Problems solved by technology

Current treatments for cancer have limited effectiveness and a number of side effects.
However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions.
Moreover, NSAIDs merely treat the symptoms of disorder and not the cause.
These drugs also have significant toxic effects.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.

Method used

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  • Imidazo [4,5-c]quinoline derivatives and their use in the treatment of tumors and/or inflammation
  • Imidazo [4,5-c]quinoline derivatives and their use in the treatment of tumors and/or inflammation
  • Imidazo [4,5-c]quinoline derivatives and their use in the treatment of tumors and/or inflammation

Examples

Experimental program
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Effect test

embodiments

[0059]In an embodiment, the present invention provides compounds of formula (I), wherein,

R1 is phenyl, which is unsubstituted or substituted with an alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more of the same or different groups selected from nitro, cyano, —CONH2, amino, halogen, hydroxy, haloalkyl and alkoxy;

R2 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, amino, —NHR8 or NR8R8;

R3, R4, R5 and R7 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, halogen, acyl, hydroxy, alkoxy, amino, cyano and nitro;

R6 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, halogen, acyl, hydroxy, amino, cyano, nitro, thiol, —COOH, —CONH2, —OR8, —NHR8, —SR8 or —B(OH)2;

each R8 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heteroaryl or heterocyclyl; and

Y is —C(O), —C(S) or —S(O)n; wherein n is 0, for 2;

[0060]wherein alkyl is unsubstituted or substituted with one or more...

example 1

2-(4-(8-Bromo-2-oxo-3-(4-(trifluoromethoxy)phenylsulfonyl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile

[0263]To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.12 mmol) and triethylamine 24.2 mg (0.24 mmol) in DCM (6 ml) was added 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (46.8 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.

[0264]Yield: 28 mg (18%); 1H NMR (DMSO-d6, 300 MHz): δ 9.43 (s, 1H), 8.342-8.372 (dd, 1H, J=7.2, 1.8 Hz), 7.993-8.023 (d, 1H, J=9 Hz), 7.820-7.849 (d, 2H, J=8.7 Hz), 7.756-7.793 (dd, 1H, ...

example 2

2-(8-Bromo-1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxo-1H-imidazo[4,5-c]quinolin-3 (2H)-ylsulfonyl)benzonitrile

[0265]To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.12 mmol) and triethylamine (0.36 mmol) in DCM (6 ml) was added 2-cyanobenzene-1-sulfonyl chloride (0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.

[0266]Yield: 25 mg (36%); 1H NMR (CDCl3, 300 MHz): δ 9.72 (s, 1H), 8.51-8.538 (d, 1H, J=8.7 Hz), 8.02-8.05 (d, 1H, J=9 Hz), 7.83-7.93 (m, 3H), 7.729-7.757 (d, 2H, J=8.4 Hz), 7.66-7.69 (dd, 1H, J=9, 1.8 Hz), 7.474-7.502 (d, 2H, J=8.4 Hz), 7.019...

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Abstract

The present invention provides the compounds of formula (I):The present invention relates to imidazo[4,5-c]quinoline derivatives of formula (I), process for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases mediated by phosphatidylinositol-3-kinase (PBK) and / or mammalian target of rapamycin (mTOR) and / or tumor necrosis factor-α (TNF-oc) and / or interleukin-6 (IL-6), particularly in the treatment of cancer and inflammation.

Description

FIELD OF THE INVENTION[0001]The present invention relates to imidazo[4,5-c]quinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases mediated by phosphatidylinositol-3-kinase (PI3K) and / or mammalian target of rapamycin (mTOR) and / or tumor necrosis factor-α (TNF-α) and / or interleukin-6 (IL-6), particularly in the treatment of cancer and inflammation.BACKGROUND OF THE INVENTION[0002]Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body. More than eleven million people are diagnosed with cancer every year. It is estimated that there will be sixteen million new cases every year by 2020. Cancer causes seven million deaths every year worldwide.[0003]Cancer can be defined as abnormal growth of tissues characterized by a loss of cellular differentiation. It is caused due to a deregulation of the signaling pathways involved in cell survival, cell proliferation and...

Claims

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Application Information

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IPC IPC(8): A61K31/4745A61P35/00A61P35/02A61P17/06A61P17/00A61P17/14A61P19/04A61P27/02A61P1/00A61P29/00A61P19/10A61P19/02A61P9/10A61P9/00A61P7/00A61P25/00A61P1/04A61P37/00A61P37/06A61P11/06A61P11/00C07D471/04
CPCC07D471/04A61P1/00A61P1/04A61P11/00A61P11/06A61P11/16A61P15/08A61P17/00A61P17/06A61P17/14A61P19/02A61P19/04A61P19/10A61P25/00A61P25/28A61P27/02A61P29/00A61P31/04A61P31/14A61P31/18A61P33/06A61P35/00A61P35/02A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61P7/00A61P9/00A61P9/10A61P3/10
Inventor KUMAR, SANJAYVISHWAKARMA, RAMMUNDADA, RAMSWAROOPDEORE, VIJAYKUMARKUMAR, PRAMODSHARMA, SOMESH
Owner PIRAMAL ENTERPRISES LTD